Mutations in L-type voltage gated calcium channels (LTCs) are associated with autism and other neurodevelopmental disorders. The goal of this project is to investigate how LTCs regulate neural progenitor cell (NPC) proliferation and differentiation. Neural development involves a series of coordinated events that balance maintenance and proliferation of NPCs with the differentiation of daughter cells to generate the neuronal populations that comprise the mature cerebral cortex. LTCs such as CaV1.2 convert electrical signals into calcium signals that control biochemical pathways and activate programs of gene expression in the developing nervous system. A gain of function mutation in CaV1.2 leads to Timothy Syndrome (TS), a multi- systemic disorder characterized by autism and mental retardation. Our laboratory has generated a transgenic mouse model for TS and I have found that there is a significant increase in proliferation of NPCs in the ventricular zone (VZ) of these animals. Using an in vitro system to study neuronal differentiation, I have also found that over-expression of wildtype CaV1.2 or CaV1.2 containing the TS mutation (TS-CaV1.2) results in a dramatic impairment of neuronal differentiation. Furthermore, blocking endogenous LTCs also reduces NPC differentiation in vitro. The goal of this project is to extend these initial findings by investigating both the regulation of CaV1.2 during development and the mechanisms by which these channels control NPC differentiation in vitro and in vivo. These studies will expand our understanding of how activity regulates brain development and will provide new insights into the underlying pathophysiology of autism and mental retardation. PUBLIC HEALTH RELEVANCE: Autism spectrum disorders affect more than a million children in the US. The research described here focuses on an inherited form of autism called Timothy Syndrome that is caused by a mutation in the voltage-gated calcium channel CaV1.2. This work will explore the mechanisms by which this mutation influences neurogenesis in the developing brain and will provide insights into cellular and molecular mechanisms that may cause autism in Timothy Syndrome, as well as other autism spectrum disorders.